The present invention relates to an improved process for the preparation of compounds carrying one or more phosphate groups and to intermediates therefor. In particular, the invention relates to a process for the preparation of polyalkylene glycol phosphates.
Surface active compositions comprising phosphate esters of alkoxylated alcohols are known and described, for example in U.S. Pat. No. 3,462,520. Bis-diphenyl phosphate derivatives of certain alkylene glycols for use in producing flame retardant rayon are described in U.S. Pat. No. 3,556,825. U.S. Pat. No. 3,294,873 discloses phosphorylated polyether polyols and flame-retardant polyurethane compositions derived therefrom.
Recently it has been suggested that the blood residence time of parenterally administered magnetic particles for use in MR imaging may be prolonged by chemical binding of a stabiliser substance to the magnetic particle surface (see e.g. U.S. Pat. No. 5,160,725 and WO-A-94/21240).
Examples of materials which may be used as stabilisers include carbohydrates such as oligo- and polysaccharides, polyamino acids, oligo- and polynucleotides and polyalkylene oxides. Such substances must have at least one chemically reactive functional group, such as a carboxyl, phosphate or phosphonate group, by means of which they are able to bond chemically or adsorb to the surface of the magnetic particles. In this regard, functionalised polymers, such as functionalised polyalkylene oxides, have proved particularly useful.
Organic mono- and di-phosphates are one group of compounds which are capable of forming chemical bonds with the surface of magnetic particles and which have thus been proposed for use as stabiliser substances (see e.g. U.S. Pat. No. 5,160,725). One compound which has been widely suggested for use as a stabiliser substance is a phosphorus oxide terminal polyethylene glycol, in particular, methoxy-polyethylene glycol phosphate (hereinafter referred to as methoxy-PEG-phosphate or MPP).
In the industrial manufacture of polyethylene glycol phosphate, it is important to reduce the production of undesirable by-products and to optimise the yield and purity of the final product. This in turn can lead to a substantial reduction in production costs.
We have now developed an improved process for the synthesis of compounds carrying one or more phosphate groups, especially polyalkylene glycol phosphate compounds, which process avoids the production of by-products and so greatly increases the yield. The products produced by such a process are also low in impurities.
Thus, viewed from one aspect the invention provides a process for the preparation of a compound carrying a phosphate group, said process comprising the steps of:
(a) reacting a compound containing at least one primary alcohol moiety with a diaryl- or diaralkyl-halophosphate whereby to form the corresponding diaryl- or diaralkyl-phosphate ester;
(b) reductively cleaving the resulting product; and
(c) if desired, repeating steps (a) and (b) with the product of step (b) whereby to produce a compound carrying two or more phosphate groups.
The process in accordance with the invention is conveniently a two-step process comprising steps (a) and (b) as defined above in which high yields are obtained by conducting the first reaction step under especially mild conditions.
By repeating steps (a) and (b) with the product of step (b), compounds carrying two, three or more phosphate moieties can, however, be prepared. In this way, the process of the invention can be used to prepare polymers of phosphates such as diphosphate, triphosphate and polyphosphates. Such oligo- and polyphosphates are particularly preferred for use as stabiliser substances since these are capable of binding more strongly to magnetic particles due to the presence of multiple binding sites.
Compounds containing at least one primary alcohol moiety for use in the process of the invention include alcohols having a molecular weight of at least 50, especially preferably of at least 100. Hydrophilic alcohols are particularly preferred.
Particularly preferred compounds containing at least one primary alcohol moiety include long chain polymers, such as polyalkylene oxide compounds having a molecular weight (weight average) in the range of from 100 to 200,000, preferably from 250 to 100,000, more preferably from 250 to 20,000, e.g. from 500 to 3,000.
Polyalkylene oxides suitable for use in the process of the invention may be linear or branched, preferably linear. Preferred polyalkylene oxides include polyethylene oxides, polypropylene oxides, polybutylene oxides and derivatives thereof. Particularly preferred polyalkylene oxides include polyethylene oxides, polypropylene oxides and random and block copolymers thereof. Conveniently, the number of polyethylene oxide and polypropylene oxide groups in such compounds may be from 1 to 300, preferably from 2 to 100.
Preferred derivatives of polyalkylene oxides for use in the process of the invention include the C1-8 straight-chain or branched alkoxy, preferably C1-6 alkoxy, e.g. methoxy substituted compounds.
Particularly preferably, the compound containing at least one primary alcohol moiety for use in the process of the invention is methoxy polyethylene glycol (hereinafter referred to as methoxy-PEG).
The compound carrying at least one primary alcohol moiety is preferably reacted with an equivalent molar concentration of a diaryl- or diaralkyl-halophosphate compound, particularly preferably with an equivalent molar concentration of a diaryl halophosphate compound. Whilst the diaryl- or diaralkyl-halophosphate compound for use in the process of the invention is preferably a diaryl- or diaralkyl-chlorophosphate, other diaryl- or diaralkyl-halophosphates may be used, e.g. diaryl- or diaralkyl-iodophosphates and bromophosphates.
As used herein, xe2x80x9caralkylxe2x80x9d is intended to include alkyl groups substituted by at least one aryl group, preferably an alkyl group substituted by a single aryl group.
As used herein, xe2x80x9carylxe2x80x9d is intended to include aromatic groups containing from 5 to 12, preferably those containing 5 or 6 ring atoms, optionally substituted by one or more halogen atoms and/or nitro groups, or by one or more groups selected from R, OR, SR, NHR, NR2, CO2R and CONHR in which each R independently represents a hydrogen atom or an alkyl group.
In the compounds for use in the process of the invention, any alkyl moiety, unless otherwise specified, may be straight-chained or branched and preferably contains from 1 to 8, more preferably from 1 to 6, especially preferably from 1 to 4 carbon atoms.
Aryl groups suitable for use in the invention include heterocyclic aryl groups having one or more heteroatoms selected from oxygen, nitrogen and sulphur.
Preferred aryl groups include phenyl and naphthyl.
Particularly preferred diaryl halophosphate compounds for use in step (a) include diphenyl iodophosphate, diphenyl bromophosphate and diphenyl chlorophosphate. Diphenyl chlorophosphate is especially preferred.
Preferred diaralkyl halophosphates for use in step (a) include dibenzyl halophosphates, e.g. dibenzyl iodophosphate, dibenzyl bromophosphate and dibenzyl chlorophosphate. Particularly preferred is dibenzyl chlorophosphate. Other diaralkyl halophosphates which may be used in step (a) include di-4-nitrobenzyl halophosphates, e.g. di-4-nitrobenzyl chlorophosphate.
Conveniently step (a) may be carried out in a solvent or mixture of solvents selected from methylene chloride, methanol, ethanol, acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran and dioxane. It is particularly advantageous to carry out step (a) in the presence of methylene chloride. The reaction may, however, be carried out without a solvent.
Preferably, step (a) is also carried out in the presence of an organic base, or mixture of organic bases, which may simultaneously act as a solvent. Examples of organic bases suitable for use in the process of the invention include triethylamine, N,N-diisopropylethylamine, pyridine and dimethyl-aminopyridine or mixtures thereof. A particularly preferred mixture of organic bases for use in step (a) is a mixture of triethylamine and dimethylaminopyridine.
Step (a) may be conducted at temperatures in the range of from 0 to 35xc2x0 C., preferably at temperatures from 20 to 25xc2x0 C. In general, ambient temperature is preferred.
Step (b) involves reductive cleavage of the aryl or aralkyl groups from the diaryl- or diaralkyl-phosphate ester compound produced in step (a). This is conveniently carried out hydrogenolytically at temperatures of from 25 to 50xc2x0 C., preferably from 38 to 45xc2x0 C., e.g. from 40 to 42xc2x0 C., preferably at a pressure of from 200 to 450 kPa, e.g. from 300 to 350 kPa.
Hydrogenation is preferably carried out using platinum oxide (Adam""s catalyst) at a temperature of 40xc2x0 C. and a pressure of 350 kPa. Other hydrogenation catalysts suitable for use in step (b) include palladium or platinum on charcoal.
Step (b) is preferably carried out in the presence of at least one protic solvent. Suitable protic solvents for use in step (b) are those which result in the minimal production of by-products and include organic acids, such as acetic acid, isopropanol and methanol. Acetic acid is particularly preferred. Alternatively, step (b) may be carried out in the absence of any solvent.
In carrying out steps (a) and (b) any reactive groups present, especially on the compound carrying the primary alcohol moiety, may be protected during the reaction using conventional protecting groups which may be cleaved by conventional procedures, e.g. hydrolysis, at the end of the reaction.
Conveniently, the compounds produced in accordance with the process of the invention are isolated by conventional work-up procedures and, optionally, further purified using procedures well known in the art, such as for example re-crystallisation from a solvent mixture, e.g. from tetrahydrofuran/hexanes. Other solvents which may be used in this regard include acetone, ethanol/hexanes and ethyl acetate/hexanes.
Step (a) results in the formation of a diaryl- or diaralkyl-phosphate ester compound, e.g. a diphenyl phosphate ester, which may be isolated and, if desired, further purified using conventional purification procedures. Such compounds form a further aspect of the invention.
Viewed from a further aspect the invention thus provides diaryl- and diaralkyl-phosphate ester compounds. Preferred compounds in accordance with the invention include those of formula I:
R1Oxe2x80x94PO(OR2)2xe2x80x83xe2x80x83(I)
(wherein R1 is the residue of a polyalkylene oxide having a weight average molecular weight in the range of from 100 to 200,000, preferably from 250 to 100,000, more preferably from 250 to 20,000, e.g. from 500 to 3,000; and R2 is an aralkyl, or more preferably an aryl moiety as hereinbefore defined).
Preferably, R2 is phenyl or naphthyl, particularly preferably phenyl.
Particularly preferred compounds in accordance with the invention include polyethylene glycol diphenylphosphate ester and derivatives thereof, e.g. methoxy polyethylene glycol diphenylphosphate ester.
Viewed from a yet further aspect, the invention provides a product, e.g. a compound carrying one or more phosphate groups prepared by the process hereinbefore described, and a magnetic particle, particularly preferably a superparamagnetic particle, linked to one or more of such products.
Particularly preferred compounds prepared in accordance with the process of the invention include polyethylene glycol derivatives, such as mono- and di-PEG-phosphate and alkoxy-PEG phosphates, e.g. methoxy-PEG-phosphate, methoxy-PEG-diphosphate and methoxy-PEG-triphosphate.
The process in accordance with the invention results in minimal production of undesirable by-products and a yield of the desired product in the range of from 90 to 95% by weight. Conveniently, the product produced in accordance with the process of the invention has a purity in excess of 95% by weight, preferably greater than 98% by weight.
The invention will now be further described with reference to the following non-limiting Examples and the accompanying Figures in which: